PROJECT SUMMARY/ABSTRACT: Memory complaints are widespread among the elderly and aging is a major risk factor for Alzheimer's disease (AD), leading to the impression that a gradual loss of memory ability, eventually culminating in dementia, may be a nearly universal consequence of getting old. Cycle 1 of this project explored an alternative aging trajectory by studying 80+ year olds, we labeled ?SuperAgers,? who have episodic memory performance that appears to have escaped age-related decline and that remains in the range that is at least normal for 50-60 year-olds. We enrolled a dedicated and unique cohort of participants committed to longitudinal assessment and brain donation at death. During Cycle 1 we identified domain- specific biologic, psychosocial, and genetic features of the SuperAgers, including maintenance of cortical integrity (especially in the anterior cingulate), an abundance of anterior cingulate Von Economo neurons and sparse cortical Alzheimer pathology compared to their cognitively average peers. These features may contribute in part to maintenance of superior memory performance past the 8th decade of life. Building on the findings of Cycle 1, this competitive renewal proposes to examine the SuperAging phenotype through the integrity of brain networks, gene expression, synaptic features and its resilience to AD pathology. We will also enhance our collaborative efforts by establishing an African American SuperAger cohort through a consortium. Aim 1 will focus on brain network integrity using graph theory. Aim 2 will focus on synaptic integrity, resilience to AD / other pathology, and gene expression. Aim 3 will enhance our established collaborative SuperAging resource through the collection of new data through the initiation of a harmonized multi-site study of African American SuperAgers. The proposed project will allow us to expand our unique group of SuperAgers and cognitively average peers. By identifying neurobiologic features that contribute to superior memory performance in old age, outcomes from this project will help us isolate factors that promote successful cognitive aging and perhaps also prevent age-related brain diseases such as AD. The project's reliance on a cohort that has already been partially recruited, its longitudinal design, multidisciplinary structure, and collaboration-friendly organization increases the likelihood that consequential progress will be achieved.